tbuckley/cabot-search huggingface dataset:
The Impact of Pro-Poor Sanitation Subsidies in Open Defecation-Free Communities: A Randomized, Controlled Trial in Rural Ghana
Authors: John T. Trimmer, Joyce Kisiangani, Rachel Peletz, Kara Stuart, Prince Antwi-Agyei, Jeff Albert, Ranjiv Khush, Caroline Delaire
Journal: Environmental Health Perspectives (2022)

According to the World Health Organization/United Nations International Children's Fund Joint Monitoring Program, 494 million people practice open defecation globally. After achieving open defecation-free (ODF) status through efforts such as Community-Led Total Sanitation (CLTS), communities (particularly vulnerable households) may revert to open defecation, especially when toilet collapse is common and durable toilets are unaffordable. Accordingly, there is increasing interest in pro-poor sanitation subsidies.This study determined the impacts of a pro-poor sanitation subsidy program on sanitation conditions among the most vulnerable households and others in the community.In 109 post-ODF communities in Northern Ghana, we conducted a cluster randomized controlled trial to evaluate a pro-poor subsidy program that identified the most vulnerable households through community consultation to receive vouchers for durable toilet substructures. We surveyed households to assess toilet coverage, quality, and use before and after the intervention and tracked program costs.Overall, sanitation conditions deteriorated substantially from baseline to endline (average of 21 months). In control communities (not receiving the pro-poor subsidy), open defecation increased from 25% (baseline) to 69% (endline). The subsidy intervention attenuated this deterioration (open defecation increased from 25% to only 54% in subsidy communities), with the greatest impacts among voucher-eligible households. Noneligible households in compounds with subsidized toilets also exhibited lower open defecation levels owing to in-compound sharing (common in this context). CLTS followed by the subsidy program would benefit more households than CLTS alone but would cost 21-37% more per household that no longer practiced open defecation or upgraded to a durable toilet.Sanitation declines, often due to toilet collapse, suggest a need for approaches beyond CLTS alone. This subsidy program attenuated declines, but durable toilets likely remained unaffordable for noneligible households. Targeting criteria more closely aligned with sanitation inequities, such as household heads who are female or did not complete primary education, may help to generate greater and more sustainable impacts in Northern Ghana and, potentially, other contexts facing toilet collapse and limited market access. https://doi.org/10.1289/EHP10443.
Regulation and impact of cardiac lymphangiogenesis in pressure-overload-induced heart failure
Authors: Coraline Heron, Anais Dumesnil, Mahmoud Houssari, Sylvanie Renet, Theo Lemarcis, Alexis Lebon, David Godefroy, Damien Schapman, Orianne Henri, Gaetan Riou, Lionel Nicol, Jean-Paul Henry, Manon Valet, Marie Pieronne-Deperrois, Antoine Ouvrard-Pascaud, Réné Hagerling, Hélène Chiavelli, Jean-Baptiste Michel, Paul Mulder, Sylvain Fraineau, Vincent Richard, Virginie Tardif, Ebba Brakenhielm
Journal: Cardiovascular Research (2022)

Lymphatics are essential for cardiac health, and insufficient lymphatic expansion (lymphangiogenesis) contributes to development of heart failure (HF) after myocardial infarction. However, the regulation and impact of lymphangiogenesis in non-ischaemic cardiomyopathy following pressure-overload remains to be determined. Here, we investigated cardiac lymphangiogenesis following transversal aortic constriction (TAC) in C57Bl/6 and Balb/c mice, and in end-stage HF patients.Cardiac function was evaluated by echocardiography, and cardiac hypertrophy, lymphatics, inflammation, oedema, and fibrosis by immunohistochemistry, flow cytometry, microgravimetry, and gene expression analysis. Treatment with neutralizing anti-VEGFR3 antibodies was applied to inhibit cardiac lymphangiogenesis in mice. We found that VEGFR3-signalling was essential to prevent cardiac lymphatic rarefaction after TAC in C57Bl/6 mice. While anti-VEGFR3-induced lymphatic rarefaction did not significantly aggravate myocardial oedema post-TAC, cardiac immune cell levels were increased, notably myeloid cells at 3 weeks and T lymphocytes at 8 weeks. Moreover, whereas inhibition of lymphangiogenesis did not aggravate interstitial fibrosis, it increased perivascular fibrosis and accelerated development of left ventricular (LV) dilation and dysfunction. In clinical HF samples, cardiac lymphatic density tended to increase, although lymphatic sizes decreased, notably in patients with dilated cardiomyopathy. Similarly, comparing C57Bl/6 and Balb/c mice, lymphatic remodelling post-TAC was linked to LV dilation rather than to hypertrophy. The striking lymphangiogenesis in Balb/c was associated with reduced cardiac levels of macrophages, B cells, and perivascular fibrosis at 8 weeks post-TAC, as compared with C57Bl/6 mice that displayed weak lymphangiogenesis. Surprisingly, however, it did not suffice to resolve myocardial oedema, nor prevent HF development.We demonstrate for the first time that endogenous lymphangiogenesis limits TAC-induced cardiac inflammation and perivascular fibrosis, delaying HF development in C57Bl/6 but not in Balb/c mice. While the functional impact of lymphatic remodelling remains to be determined in HF patients, our findings suggest that under settings of pressure-overload poor cardiac lymphangiogenesis may accelerate HF development.
Abstract 1210: Resolving clonal substructure from single cell genomic data in primary and metastatic tumors using CopyKit
Authors: Darlan Conterno Minussi, Junke Wang, Aislyn Schalck, Yun Yan, Hua-Jun Wu, Cheng Peng, Min Hu, Emi Sei, Mary Edgerton, Hui Chen, Alejandro Contreras, David Hui, Senthil Damodaran, Scott Kopetz, Bora Lim, Nicholas Navin
Journal: Cancer Research (2022)

Abstract Advances in single cell copy number sequencing technologies have enabled the generation of data on hundreds to thousands of cells in parallel. Despite the rapid development in these technologies, there is a significant bottleneck for the analysis of the resulting large-scale datasets. Here we present CopyKit, a comprehensive and user-friendly toolkit for the analysis of single cell copy number data. CopyKit provides a suite of tools for pre-processing, QC, copy number inference, and subclone clustering to delineate the clonal diversity of tumors. We performed single cell copy number sequencing of 2977 cells from two breast tumor liver metastasis. CopyKit identified 4 and 12 subclonal populations, including amplification of PDGFRA, KRAS, and MYC as well as losses of PTEN, FOXO1, RB1, and BRCA1, many of which were spatially segregated in the tumor mass of the two tumors. Additionally, we applied CopyKit to study metastatic dissemination from a primary ER+ breast tumor with two matched metastatic sites and two colorectal carcinomas with matched liver metastatic tissues. This analysis demonstrated that the breast metastatic tumors selected for subclones that were lacking ERBB2 amplification in the primary site. Furthermore, the liver metastasis had deletions of chromosomes 18, 19, and 20p and a focal gain of FGFR1, while the pleural effusion acquired two additional focal gains on chromosome 8, including MYC. The colorectal metastatic tumors diverged from the primary tumor with copy number events affecting important cancer genes such as gain of SOX4, MYC, CDK8 and deletions of FHIT, CHEK1, and CHEK2. Collectively, this study shows that CopyKit provides a comprehensive set of tools for resolving clonal substructure from single cell copy number data for diverse applications in cancer biology. Citation Format: Darlan Conterno Minussi, Junke Wang, Aislyn Schalck, Yun Yan, Hua-Jun Wu, Cheng Peng, Min Hu, Emi Sei, Mary Edgerton, Hui Chen, Alejandro Contreras, David Hui, Senthil Damodaran, Scott Kopetz, Bora Lim, Nicholas Navin. Resolving clonal substructure from single cell genomic data in primary and metastatic tumors using CopyKit [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1210.
Abstract 1799: Inhibition of triple negative breast cancer metastasis <i>via</i> Enolase-1 modulation
Authors: Dhanir Tailor, Arpit Dheeraj, Fernando Jose Garcia-Marques, Mallesh Pandrala, Abel Bermudez, Sharon Pitteri, Sanjay V. Malhotra
Journal: Cancer Research (2022)

Abstract Triple-negative breast cancer (TNBC) is one of the aggressive forms of breast cancer and frequently relapses and metastases. Currently, very few options are available for TNBC treatment. Cancer cells exploit glycolytic machinery for the Warburg effect and aerobic glycolysis. Enolase 1 (ENO1) is the glycolytic enzyme expressed in the majority of tissues and many cancer cells have its higher expression. Apart from the glycolytic role in the cytosol, ENO1 also plays different roles in cancer cells including function as a surface receptor. We have developed a chemical small molecule (CET12) that strongly binds to ENO1 and restrain its activity and subcellular localization. CET12 treatment arrests the TNBC cells in the mitotic phase and leads the apoptotic cell death via AMPK activation. Global proteome profiling suggested that CET12 pushes the cells toward oxidative phosphorylation. It also inhibits cell migration and invasion in vitro. In vivo studies using 4T1 and EMT6 syngeneic mouse models are also in-line with in vitro results and revealed that SU0212 treatment inhibits tumor progression and metastasis. These results were further supported by tail vain lung metastasis assay and intracardiac injection mouse model. This study provides compelling preclinical data for further development of CET12 for the treatment of TNBC. Citation Format: Dhanir Tailor, Arpit Dheeraj, Fernando Jose Garcia-Marques, Mallesh Pandrala, Abel Bermudez, Sharon Pitteri, Sanjay V. Malhotra. Inhibition of triple negative breast cancer metastasis via Enolase-1 modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1799.
Abstract 1691: The landscape of intra-tumor heterogeneity (ITH) and its association with actionable mutation and blood tumor mutation burden (bTMB) in patients with non-small cell lung cancer (NSCLC) assessed by circulating tumor DNA (ctDNA)
Authors: Leeseul Kim, Yeun Ho Lee, Hye Sung Kim, Horyun Choi, Jinah Kim, Young Kwang Chae
Journal: Cancer Research (2022)

Abstract Background: ITH, which is caused by subpopulations of cells with distinct genomic alterations within the same tumor is known to have an impact on the biological profile and natural history of the tumor. However, assessment of ITH is mostly done tissue-based. Herein, we investigated the correlation of ITH assessed by ctDNA with bTMB and the presence of actionable mutations. Method: Blood samples were collected from consecutive 53 patients with NSCLC seen at Northwestern Memorial Hospital. For each sample, SNV, indel, and CNV results generated by sequencing of all plasma ctDNA (Guardant360) were formatted for PyClone. ITH scores were calculated using the number of clusters identified in the sample divided by the number of variants detected in the sample. Result: bTMB was evaluable for 22 patients (41%). 7 patients (13%) had actionable mutations associated with FDA-approved therapies. Cluster number was positively correlated with bTMB (Pearson r 0.69, p-value 0.0004, CI 0.38 to 0.86) and was negatively correlated with the presence of actionable mutations (median 2 vs 5, p-value 0.01). ITH scores were not significantly correlated with bTMB (Pearson r 0.03, p-value 0.89, CI -0.39 to 0.44). Conclusion: Higher cluster number was inversely correlated with the presence of actionable mutations and positively correlated with bTMB. Our study illustrates the importance of utilizing liquid biopsy to assess ITH with tissue-based ITH in clinics for a better understanding of the biological profile of tumor. Citation Format: Leeseul Kim, Yeun Ho Lee, Hye Sung Kim, Horyun Choi, Jinah Kim, Young Kwang Chae. The landscape of intra-tumor heterogeneity (ITH) and its association with actionable mutation and blood tumor mutation burden (bTMB) in patients with non-small cell lung cancer (NSCLC) assessed by circulating tumor DNA (ctDNA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1691.
Abstract 317: Isolation of highly selective antibodies against claudin 18.2 for the treatment of solid tumors
Authors: Brad Screnci, Trevor Barnes, Kristen Shema, Rebecca Rimkunas, Shruthi Kannan, Tim Phillips, Carmen Navia, Charles Azuelos, Tom Charpentier, Jennifer Houtmann, Lisa Miller, Lewis J. Stafford, Benjamin J. Doranz, Joseph B. Rucker, Ross Chambers
Journal: Cancer Research (2022)

Abstract Monoclonal antibodies (MAbs) are a well-established treatment approach in oncology and other diseases. Nevertheless, many multipass membrane proteins are largely inaccessible as antibody targets due to their poor expression, membrane-dependent structure, small extracellular regions, and high sequence conservation between humans and rodents. Integral Molecular’s MPS Antibody Discovery platform specifically addresses each of these challenges. A key enabling feature of MPS is the use of chickens as an evolutionarily divergent host species for immunization, allowing a more robust immune response for targets that are highly conserved in mammals. We will present on antibodies isolated against challenging membrane protein targets in oncology including Claudin 18.2 (CLDN18.2).CLDN18.2 is a transmembrane adhesion protein undetectable in most adult healthy tissues but highly expressed in gastric, pancreatic, esophageal, and lung cancers. Antibody discovery efforts against this validated target are challenging due to the abundant expression of the splice isoform CLDN18.1 differing by only 8 amino acids in the extracellular domain. As part of the MPS platform, we used virus-like particles (Lipoparticles) to immunize chickens with a high concentration of native CLDN18.2 protein and obtain high-titer immune responses. This enabled us to generate and isolate a large and diverse collection of MAbs (48 unique clones) and select candidates for optimization. We present a panel of three highly specific, humanized CLDN18.2 MAbs with picomolar affinities that are superior to the clinical-stage benchmark. We will show in-depth profiling data for the MAb panel that were used for lead selection and de-risking clinical development. These data include biosensor binding kinetics, amino-acid resolution epitope mapping, and specificity testing against the Membrane Proteome Array (MPA) consisting of 6,000 membrane proteins. This panel of preclinical antibodies are being developed for therapeutic use in various formats, including bispecifics, antibody-drug conjugates, and CAR-T applications. Citation Format: Brad Screnci, Trevor Barnes, Kristen Shema, Rebecca Rimkunas, Shruthi Kannan, Tim Phillips, Carmen Navia, Charles Azuelos, Tom Charpentier, Jennifer Houtmann, Lisa Miller, Lewis J. Stafford, Benjamin J. Doranz, Joseph B. Rucker, Ross Chambers. Isolation of highly selective antibodies against claudin 18.2 for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 317.
Abstract 598: A novel allosteric CBL-B inhibitor with differentiated immune enhancing activity in preclinical models
Authors: Yilin Qi, Jun Kuai, Yingzhi Bi, Huadong Sun, Deborah G. Conrady, Rajiv G. Govindaraj, Graham Hone, Rajiah A. Denny, Ken Carson, Timothy Reilly, Geraldine Harriman, Fang Wang
Journal: Cancer Research (2022)

Abstract E3 ligase Casitas B-Lineage Lymphoma Proto-Oncogene B (CBL-B) is a key negative modulator of T-cell receptor and co-stimulatory regulation. CBL-B inhibition lowers the threshold of antigen-specific T cell activation, even in absence of co-stimulatory signaling or the presence of an immune suppressive environment. Genetic ablation of Cbl-b or functional inactivation of its E3 ligase activity in mice or primary human T cells enhances immune-mediated tumor growth control. Therefore, CBL-B inhibition may address the suboptimal response to current immunotherapies due to low inflammation, no/low co-stimulation signal or a high immune suppressive environment. We have identified a series of potent allosteric CBL-B inhibitors via the application of our proprietary Smart Allostery࣪ platform. Herein we demonstrate one of our lead CBL-B inhibitors showed superior activity compared to a competitor CBL-B inhibitor (NX-519) in both biochemical and cellular assays. At similar exposures in a syngeneic mouse tumor model (CT26), our CBL-B inhibitor also demonstrated an increase in tumor growth inhibition relative to NX-519. Mechanistically, our CBL-B inhibitor not only enhanced T cell activation, but also re-invigorated exhaustive T cells and caused resistance to T regulatory cell-mediated suppression, both in a concentration-dependent manner. We further demonstrated differentiation of CBL-B inhibition versus anti-PD1 and anti-CTLA4 in the mixed lymphocyte reaction (MLR) assay. Our CBL-B inhibitor significantly promoted T cell proliferation where anti-PD1 alone and anti-CTLA4 alone did not. Both anti-PD1 and CBL-B inhibition increased IFNγ production in this MLR assay, but that effect was further enhanced in combination. Together, the pre-clinical data presented here provided evidence of a differentiated profile of our allosteric CBL-B inhibitors to enhance key parameters associated with T cell activation and reduce susceptibility to immune suppression, supporting their further progression toward clinical development. Citation Format: Yilin Qi, Jun Kuai, Yingzhi Bi, Huadong Sun, Deborah G. Conrady, Rajiv G. Govindaraj, Graham Hone, Rajiah A. Denny, Ken Carson, Timothy Reilly, Geraldine Harriman, Fang Wang. A novel allosteric CBL-B inhibitor with differentiated immune enhancing activity in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 598.
Impact of acute exacerbations of COPD on patients' health status beyond pulmonary function: A scoping review
Authors: A. Machado, M. Barusso, J. De Brandt, K. Quadflieg, S. Haesevoets, M. Daenen, M. Thomeer, D. Ruttens, A. Marques, C. Burtin
Journal: Pulmonology (2022)

This scoping review summarized the evidence regarding the impact of acute exacerbations of COPD (AECOPD) on patients' health status beyond pulmonary function. PubMed, Embase, and Web of Science were searched. Prospective cohort studies assessing the health status of patients with COPD in a stable phase of the disease and after a follow-up period (where at least one AECOPD occurred) were included. An integrated assessment framework of health status (i.e., physiological functioning, complaints, functional impairment, quality of life) was used. Twenty-two studies were included. AECOPD acutely affected exercise tolerance, quadriceps muscle strength, physical activity levels, symptoms of dyspnoea and fatigue, and impact of the disease. Long-term effects on quadriceps muscle strength, symptoms of dyspnoea and depression, and quality of life were found. Repeated exacerbations negatively impacted the fat-free mass, levels of dyspnoea, impact of the disease and quality of life. Conflicting evidence was found regarding the impact of repeated exacerbations on exercise tolerance and physical activity levels. AECOPD have well-established acute and long-term adverse effects on health status beyond pulmonary function; nevertheless, the recovery trajectory and the impact of repeated exacerbations are still poorly studied. Further prospective research is recommended to draw firm conclusions on these aspects.
Abstract 4256: YH012, a novel bispecific anti-HER2 and TROP2 antibody-drug conjugate, exhibits potent antitumor efficacy
Authors: Chengzhang Shang, Liu Yang, Jiyong Zhang, Yanfei Han, Zhuolin Li, Zhenyan Han, Jun Li, Ying Meng, Gao An, Hao Yang, Wenqian An, Lei Chen, John Charpentier
Journal: Cancer Research (2022)

Abstract Bispecific antibodies (BsAbs) and antibody-drug conjugates (ADCs) are among the most promising and fastest growing classes of next-generation antibody therapeutics for cancer therapy. The strategy of targeting dual tumor-associated antigens (TAAs) with a BsAb offers several advantages, such as improved efficacy due to synergistic effects, increased target cross-linking and internalization, increased tumor cell specificity and reduced side effects in normal tissues. HER2 is an established therapeutic target for approximately 20% of breast cancers, and its overexpression has been observed in a variety of other solid tumors. Trop-2 is another ideal tumor-associated target overexpressed on a wide variety of solid tumors. Co-expression of HER2 and TROP2 has been found in a number of tumors including gastric, colorectal, bladder and breast cancers. Therefore, co-targeting these TAAs using bispecific antibodies has clinical potential. YH012 is a novel first-in-class bispecific antibody-drug conjugate targeting HER2-TROP2 (HER2-TROP2-ADC), which contains a novel fully human bispecific anti-HER2/TROP2 antibody conjugated with Monomethyl auristatin E (MMAE) via a protease-cleavable linker. The anti-HER2/TROP2 BsAb showed increased endocytosis activity compared with its parental mAbs in tumor cells co-expressing HER2/TROP2, whereas the monovalent HER2 or TROP2 antibodies showed reduced internalization. As expected, YH012 showed increased in vitro potency of cell killing compared to the monovalent HER2/TROP2-ADC. These results suggest that YH012 increases the selectivity of payload delivery demonstrating the beneficial effects of targeting dual TAAs using BsAb-ADC. Moreover, YH012 showed robust anti-tumor efficacy in multiple cell line-derived none-small cell lung cancer (NSCLC) and gastric xenografts. Treatment with YH012 showed sustained tumor growth inhibition, which is more pronounced than the effects of the parental mAb-ADCs and monovalent ADCs. These preclinical data suggest that YH012 could potentially benefit patients with tumors co-expressing HER2 and TROP2 through improved drug selectivity and efficacy. Further investigations on the antitumor activity and safety profile of YH012 are ongoing in dogs. Citation Format: Chengzhang Shang, Liu Yang, Jiyong Zhang, Yanfei Han, Zhuolin Li, Zhenyan Han, Jun Li, Ying Meng, Gao An, Hao Yang, Wenqian An, Lei Chen, John Charpentier. YH012, a novel bispecific anti-HER2 and TROP2 antibody-drug conjugate, exhibits potent antitumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4256.